Photodynamic therapy (PDT) involves the use of light energy in the treatment of one or more afflictions. The field is broad enough to encompass light in a variety of forms from visible light to organized light energy such as that emitted by lasers. Such treatments can be used as an alternative to traditional chemotherapy and surgical treatments and thereby avoid the side effects and drawbacks associated therewith.
Early work in the 1970's, followed by rapidly expanding studies in the 1980's, has shown that photodynamic therapy (PDT) offers a viable, less toxic and generally less painful avenue to treatment of certain lesions. In PDT, photosensitizing dyes are administered to a patient and localize in neoplastic tissues. The great majority of the earlier PDT agents studied have been derived from natural sources (porphyrins, chlorins, purpurins, etc.) or from known chemicals originating in the dyestuffs industry (e.g., cyanine dyes). For more recent PDT agents derived from natural sources see U.S. Pat. Nos. 4,961,920 and 4,861,876. Synthetic efforts have focused on porphryinoid compounds which are highly absorptive in the longer wavelength range of about 600-1200 nm, where the transparency of tissue is higher. Compounds such as purpurines, naphthocyanin silicon complexes, chlorins, bacteriochlorins, and substituted phenylporphyrins have been prepared and tested in vivo. Additional PDT agents are described in EP 276,121 and Weinstein et al. U.S. Pat. No. 4,753,958 (the disclosure of which is herein incorporated by reference).
Irradiation of the porphyrinoid dye with light at a wavelength which corresponds to an absorption band of the dye results in destruction of the neoplastic vascular tissue. The use of a fiber optic laser light source is described in U.S. Pat. No. 4,957,481. PDT has been used to treat a variety of tumors including bladder, bronchial, bone marrow and skin tumors as well as severe psoriasis.
Dougherty et al (Cancer Res., 1978, 38:2628; Photochem. Photobiol, 1987, 45:879) pioneered the field with infusion of photoactivatable dyes, followed by appropriate long wavelength radiation of the tumors (600+nm) to generate a lethal shortlived species of oxygen which destroyed the neoplastic cells. Early experiments utilized a mixture termed hematoporphyrin derivative (HPD). The deficiencies of HPD, especially prolonged phototoxicity caused by retained HPD components in human skin led to its displacement by a purified fraction termed dihematoporphyrin ether (DHP) which, although yielding improvements over HPD, nevertheless still suffered certain, practical limitations. Relatively weak absorption in the wavelength range above 600 nm, retention in dermal cells (potentially leading to phototoxicity), only modest or low selectivity for tumor cells versus other cell types in vital organs, the inability to use available, modern, inexpensive diode lasers, and uncertain chemical constitution of the mixtures are all known negative features of DHP and HPD. In animal and cell culture experiments one observes, following PDT, depending on the incubation time, damage to the vasculature, cell membranes, mitochondria and specific enzymes. See, U.S. Pat. No. 5,179,120.
Prior efforts with PDT have been directed at neoplastic tissue destruction with the energy of the laser. Such therapy has, however, had limited success due to the damage caused to surrounding tissues from the high laser energies required to destroy the target tissue. It would be useful to have a method for treating neoplastic vascular tissues that did not require such high applied energy levels or which was accompanied by damage to adjacent non-target tissues.
Weinstein et al. U.S. Pat. No. 4,753,958 teaches the PDT treatment of hyperproliferative epithelial diseases with phototoxic levels of hematoporphyrin in a topical formulation. The sensitizer was determined to inhibit DNA synthesis in treated tissues following photoactivation. To block cell division in the diseased tissue, sensitized tissue is irradiated in its entirety with a radiation source selected from UVA, fluorescent light, high intensity incandescent light, 1600 and 5000 Watt xenon arc lamps, red dye lasers, or a slide projector filtered to pass light of wavelengths no longer than 600 nm. The examples show that the illumination source is broadly directed to the entirety of the light sensitized tissue area to activate a cytotoxic response in the diseased tissue. The applied DHP is activated under the effects of light produces free radicals or singlet oxygen molecules. These produce cytotoxic oxygen products which, in turn, produce a cyto-destructive effect in abnormal human tissues.
Unfortunately, the broad area treatment taught by Weinstein et al. requires a power and a dispersion area sufficient to activate a cytotoxic response throughout the treated tissue. The laser energy required for such an affect is about 30-370 J/cm.sup.2, typically about 320 J/cm.sup.2 although the precise radiation dose is not considered to be critical. See, Weinstein et al. in column 8, lines 47-48. Such a dispersion pattern affects nontarget tissues immediately surrounding the target tissue.
It would be desirable to have a photodynamic treatment that was highly specific to the desired target tissues.
Additionally, Weinstein et al. is limited to the treatment of external epithelial tissues. Certain lesions occur in tissues (e.g., mucous membrane tissues like ocular tissue and gastrointestinal tract tissues) that do not contain cutaneous epithelial cells would benefit from photodynamic therapy as would tissues exposed surgically, e.g., nerves, muscles, and tumors. It would be desirable to have an effective photodynamic treatment therapy for tissues other than epithelial tissues.
Corneal neovascularization (CNV) is a major problem in corneal disease. Corneal vessels are always anatomically abnormal and represent a disease process. Abnormal blood vessels may form in the cornea from physical insult and injury, infections, chemical burns, corneal allograph rejection, prolonged hypoxia from chronic abusive contact lens use, or from chronic immunological activation as seen in herpetic stromal keratitis. These new corneal vessels can be at any depth within the cornea. In severe cases, the vessels can impinge upon the visual axis or produce abnormal exudates, thus affecting vision.
Patients with CNV are predisposed to a marked increase in the risk of corneal allograft rejection. The abnormal vessels provide circulating lymphocytes with ready access to donor cornea that would otherwise be granted immune privilege away from the normal conjunctival vascular arcades. Patients with CNV may have allograft survival rams as low as 35% compared with the more typical 90% rate. Thus, CNV represents one of the most important risk factors for corneal allograph rejection.
Laser treatments have been attempted for ablating individual corneal vessels. In practice, however, this therapy failed to produce favorable long term results because the energy required to coagulate CNV is so intense that subsequent inflammation may actually induce the formation of additional CNV.
It would be desirable to have a treatment for CNV that would be effective and without injury to the adjacent healthy corneal tissue.
Unfortunately, established CNV is very difficult to eradicate. New vessels may remain to the detriment of the patient even when the initial stimulus for CNV formation is removed.